Organic compounds and process



United States Patent -i 2,s44;60's URGANH', GUMPOUNDS PRGCESS Iiaymohd LPiedeison, Kalamazoo Township, Kalamazoo County, Mich., assigifdr fofIhe Upjohii company, Kalaniazo'a, Mich, a corporation of Michigan No Drawing. Application October 10, 1955 Serial No. 539,671

'21 Claims. (dim-597.47)

The present invention relates to a novel process for the prediction of 1 7-ke'to'st'eioid's and is more particularly concerned with a process of producing 17-ketosteroids selected from the group consisting of 3-o'xygenate d 17- ketoa'ndrost'anes and 17-k'etoetiocholanes, the intermediate 20-halohisnorchol an-fl-als selected from the group consi sting 3-Ketobisnor-20-halo-4-cho1 en-22 als'; 3-ketobisno'r-2f0 halocho1ai1-22-a1s; 3-ketoa11obisnor-20-ha1ocho- 1an-2 2-a1; 3-hydrokybisnor-20 haIochoIah-ZZ aIs and 3- acyIOXyBi'snOr-Z O-halocholan-22-als; s-h' droxyauo isnsr- 20-ha1o 'cholan 2 2-a'1 and 3-acyloxyallobisnor-zfl-halocho1'an-22-al s; 3-hydroXybishor-20-ha1o-5-cholen 22-a1 and 3-acyioxybisnor-20-halo-5 cholen-22-als; 3,11-diketobisnor2 -halo-4-eholen-22-al; 3 ke tobisnor-11ot-hydroXy-2O- ha1o-4 cholen-22 a1, 3-ke tobisnor-1lfi-hydtoXy-ZO-halo-4- cholen-22-al and 3,6-diketobisnor-20 halocholan-ZZ-als, wherein the halogen atom has an atomic weight of 34 to 81, inclusive, and wherein the acyl group is of an organic 'carboir yli'c acid containing from one to eight carbon atoms, inclusive; 17(20);bisnorcholen-22-als, and a process of production thereof.

H The novel process and the new intermediates II and III may be illustratively represented by the following equations:

CH3 CHr-OH:

'OHa H pounds are -preferably oxygenated in the 3-position that Patented July 22, 1958 is substituted in the three position by liydro y, a loxy, wherein the acyl group is of an organic carboirylic acid containing from one to eight carbon atoms and preferably from a hydrocarbon ca'rb'oirylic acid containing from one to eight carbon atoms, inel'us'ive, errata groups; in addition to a 3-oxyge'nate"d group, the lT-keto'sterfl ds or the ahd'r'os'tane series may be ox genated in other positions especially on the 11'-carb'on atom.

Similarly, the term '17'-k'e'tos"teroids of the etiocholane series is used to refer to these compounds of the etiocholan'e series having a 17-ket'o group. According to the invention, these compounds may also have double bonds in positions 1, 6(7), and the like and may he oxygenated in position 3, having a 3-hydroiry, acyloiiy, defined as above, or keto group. In addition the 17- ketosfe'roid of the etiochol'ane series can be substituted by keto groups especially in positions 6, 11, and the like.

The process of the present invention comprises: tr'eating a ZZ-(N te'rtiaryamiriO)-bisrioreho larie "(1), dissolved in an organic solvent, with halogen, such as bromine and chlorine or with a halogen releasing agent such as an N-haloacetylamide in acid solution, to give the corresponding 2O-halo-bisnoroholan 22-al (II), dehydrohalogeriating the 20-ha1o=hinorcho1ai1-22-al By heating with a tertiary amine, such as N-methylpiperidine, pyridine, trie'thylaniine, collidine, or the like; to obtain a 17(20)- bisnorcholen-2-2 al (III) and ezsnsi 'zi'ng the 17(20)- bisnoreholen-22-al to obtain the corresponding '17-ke'tosteroid of the 'androstane series or of the etioehol'a'ne 'seri es '(IV).

It is an object of the present invent-ion to (provide a method for the production of l7-ket er steroids of the andros't'ane and etiocholane series from the corresponding bisriorch'olane en'arnines, produced from readily available bisnorcholane aldehydes. It is another object of the instant invention to produce useful steroid intermediats belonging to the class of 20-ha'ld-bisnorc'holan-22- als selected from the group consisting "of the 3 ketobis'hor- 20-h'a'1'o4-ho1n-22-a1, 3-ketohisnor 2(i lfietlocholan iflals, 3-ket'oallobisnor20 ha1oeho1an-22-ai, the 3-liyd'r'oiry fand 3-acyIoXybisnOr ZO haloeholan 22-als, 3-hydroiiyand 3- acylo'i'ryallobisnor-20- haiochoIan ZQ-aI, the 3=hydroiiyand 3-acy1oXybisnor-20halo-5-cholen-22 als, the 6- and '11"- hydroxy, aeyloXy and keto derivatives "thereof, wherein the acyl group is of an organic earbokylic acid containing from one to eight carbon atoms, ifiolti's iv e, and piererably of -a hydrocarbon carbo rylic acid containing "from one to'eight carbon atoms, and wherein the halogen has anatomic weight between 34 and 81. It is another object of the instant invention to provide a process for the production of the dehydrohalo derivatives of the foregoing compounds, the new class of 1'7-(20)'-"hi'snorchole'n-22-a1s, such as especially s-ketdbisner nginzmcho 1adien-22-al, 3'-ketobisnor- 17(20') cholen-22-al, 3hy- 'droXyana 3-acyloXybisnor-17(2Q') chdlirZZ-bll, 3-hy dro'Xyand 3-ay1oxy'bi's'n0r-5 17 20) -Cl10ladi1i-22'3LIS "wherein the acyl group is defined as above, and the '6- and ll-hydroxy, acyloiiy and keto derivatives thereof. Other objects of the present invention 'will he apparent to those skil1dinthe art 'to Whichthisirlveiliionpertainsv The intermediates and the process of the present invention are useful for the pro'ductio'n of physiologically active compounds. Thus from the 22 en'a'rriines of 3- ketohisnor 4-choien-22 a1 there are obtained in sequence (cf. Examples 1 3 3 ketobishor i0 halo=4 eholen-22 al, 3-k'etobisnor-4,'l7(20) eholadien-22-al, and finally 4- andro steii e-oflldioli e possessing iidifbgiii properties and being an intermediate in the production of testosterone. 3,l1-diketobisnor-4-cholen-22-a1 ZZ-enamine by and 3-keto 11/8 hydroxybisnori-cholen-ii-al 22-mthe amines which yield lla-hydroxyand l15-hydroxy-4- androstene-3,l7-dione which have androgenic and anabolic activity and are oxidizable by chromic acid in acetic acid to adrenosterone; 3a or 3,6-hydroxybisnorcholan-22-al 22-enamine give anesthetically active 30;- or 3fl-hydroxyetiocholan-l7-one; 3,11-diketobisnorcholan-22-al 22-enamine gives etiocholane-3,l1,20-trione (general anesthetic activity); 3-hydroxyor 3-acyloxy-6- ketobisnorcholan-ZZ-al 22-enamine provide the corresponding 3-hydroxyetiocholane-6,l7-dione and 3-esters thereof which are oxidized (in case of a 3-ester, after hydrolysis) to the corresponding etiocholane-3,6,l7-trione, brominated to 4-bromoetiocholane-3,6,17-trione and dehydrobrominated to give 4-androstene-3,6,17-trione of estrogenic activity. Similarly the etiocholane-3,6,17- trione from which 4-androstene-3,6,17-trione is prepared may also be prepared from 3,6-diketobisnorcholan-ZZ-al 22-enamine. 3,1l-bisnorallocholan-22-al 22-enamines yield androgenically active androstane-3,l1,l7-trione.

The starting compounds of the present invention are 22-(N-tertiaryamino)-bisnorcholanes wherein the tertiary amino radical is preferably of the formula:

in which n and n are whole numbers from one to two,

inclusive.

The preferred 22-(N-tertiaryamino)-bisnor-20(22)- cholenes are selected from the group consisting of 22- (N tertiaryamino) bisnor 4,20(22) choladien 3- ones, 22 (N tertiaryamino) allobisnor 20(22) -cholen- 3-ones, 3-hydroxyand 3-acyloxy-22-(N-tertiaryamino)- bisnor-20(22)-cholen-3-ones, S-hydroxy and 3-acyloxy- 22 (N tertiaryamino) allobisnor 20(22) cholen 3- ones, S-hydroxyand 3-acyloxy-22-(N- tertiaryamino)- bisnor-5,20(22)-choladien, 3-hydroxyand 3-acyloxy-22- (N-tertiaryamino) -bisnor-5,20 (22) -choladien-1 l-ones, 3- hydroxyand 3-acyloxy-22-(N-tertiaryamino) -bisnor- 4,20(22)-choladien-6-ones, wherein the acyloxy group is of an organic carboxylic acid having from one to eight carbon atoms and wherein the tertiary amino radical is defined as before. Such enamines are prepared by the methods shown by Herr and Hey], I. Am. Chem. Soc. 74, 3629 (1952) from the corresponding bisnor-cholanaldehyde. Many of the bisnorcholan aldehydes are known and readily available, while other bisnorcholan aldehydes may be obtained by reduction of the corresponding bisnorcholanic acid as shown in the preparations. Representative starting steroids thus used comprise: the 22-N-piperidyl, 22-N-pyrrolidyl, 22-N- morpholinyl, 22-N-homorpholinyl enamines of bisnorcholan- 22-al, 3-acetoxybisnorcholan 22 al, 3 hydroxybisnorcholan 22 al, 3 benzoyloxybisnorcholan 22 al, 3- methoxybisnorcholan 22 al, 3 ketobisnorcholan 22-al, 3 ketoallobisnorcholan 22 al, 3 ketobisnor 4- cholen 22 al, 3,8 hydroxybisnor 5 cholen 22 al, 3 acetoxybisnor 5 cholen 22 al, 3,11 diketobisnor- 4 cholen 22 al, 3,11 diketobisnorcholan 22 al, 3,11 diketoallobisnorcholan 22 al, 3 keto 11ozhydroxyand 1lfl-hydroxybisnor-4-cholen-22-al, 3,6,-diketobisnorcholan-ZZ-al, 3-hydroxyand 3-acyloxy-6-ketobisnorcholan 22 al, 3 acetoxybisnorallocholan 22 a1, 3-ketobisnorallocholan-ZZ-al, maleic anhydride adduct of bisnor-5,7-choladien-22al3 8-01, and the like.

In carrying out the process of the present invention selected 22-N-tertiaryaminobisnor-Z0(22)-cholen, preferably dissolved in an organic solvent such as ethyl acetate, carbon tetrachloride, methylene dichloride, ethylene dichloride, chloroform, dioxane, tertiary butyl alcohol, dimethylformamide, methanol, ethanol,- acetic acid, and the like,,is reacted with the selected halogen dissolved in a similar organic solvent. The temperature of the reaction is between minus eighty degrees and room temperature, up to thirty degrees centigrade. In

the preferred embodiment of the invention a temperature between minus thirty and plus fifteen degrees centigrade is preferred.

With very low temperatures, instead of the ZO-bromobisnorcholan aldehyde, a 20-bromo-22-quaternary ammonium bisnorcholane halide is produced as shown in Example 1A. These quaternary ammonium compounds while stable when solid, melt and are unstable at room temperature. In a solution of an organic solvent such as in ethanol, methylene dichloride, chloroform, carbon tetrachloride solution, and in the presence of water, they split off the quaternary ammonium group and thus are converted to 20-halobisno1'cholan aldehydes.

Instead of using solutions of the free halogen, halogenation can be effected by producing the halogen molecule in situ such as, for example, by allowing to react in the solution of the enamine, an N-haloacylamide such as N-bromoacetamide, N-bromosuccinimide, and N- chlorosuccinimide with a dilute acid such as dilute hydrochloric, dilute sulfuric, dilute perchloric, dilute periodic, and other acids. The proportion of halogen or halogen releasing reactant is usually close to the calculated theoretical amount; that is, about a mole of the halogen is used for each mole of enamine. Smaller or larger proportions are operative but no additional advantage is obtained. Upon termination of the reaction, the product is isolated from the reaction mixture by conventional means such as elimination of the excess of inorganic agents by washing with suitable reagents, for example, sodium bisulfite, a dilute basic reagent such as sodium bicarbonate, dilute sodium hydroxide or potassium hydroxide solution and water and thereafter extraction with water-immiscible solvents such as ether, methylene dichloride, chloroform, and the like, evaporation, crystallization, or chromatography as deemed necessary to obtain the ZO-halobisnorcholan compounds.

The dehydrohalogenation of 20-halobisnorcholanaldehyde thus produced is accomplished by heating the 20-ha1obisnorcholan aldehydes with a tertiary amine such as pyridine, collidine, picoline, triethylamine, isoquinnoline or substituted acyl amides such as dimethyl formamide, diethyl formamide, or the like. The preferred and most convenient reagent for carrying out the dehydrohalogenation is pyridine. In the dehydrohalogenation it is advantageous but not necessary to use lithium salts such as lithium chloride or lithium bromide. These salts have an accelerating affect on the dehydrohalogenation. The dehydrohalogenation reaction is usually carried out between about fifty degrees centigrade and the reflux temperature of the selected solvent. With pyridine a temperature between sixty to degrees is preferred. The time of the reaction is not critical and is generally between one-half hour and six hours depending upon the temperature. The thus-obtained products, bisnor-17(20)-cholen-22-als are isolated by suitable conventional means such as diluting the reaction mixture with water, separating the water layer from the organic layer, washing the organic layer, concentrating the organic layer to leave the bisnor-17 (20)-cholen-22-al as a residue which can be purified in the conventional manner such as recrystallization, washing and extracting and/or chromatography.

The thus-obtained bisnor-l7(20)-cholen-22-als are then subjected to ozonolysis. In the preferred embodiment of the invention the ozonolysis is efiected in standard ozonization equipment and at low temperatures such as minus eighty to plus ten degrees centigrade. At the termination of the ozonization procedure the thus-obtained l7-ketoandrostane or 17-ketoetiocholane material is separated by conventional means such as by washing the reaction mixture, solvent extraction with water immiscible solvents as mentioned before, recrystallization, and/or chromatography as deemed necessary.

'The following examples are illustrat iye .of the process a water trap connected to the reflux condenser. There-' after the n'rixtiite was condensed under vacuum and the crystals femaining in the reaction flask were repeatedly recrystallized from benzene to give pure 3-acetoxy-22- (N homomorpholino) bisnor 5,7', (22) cholatrien- 5,8-diin'ethyl maleate adduct.

Otherwise like Preparation- 1, by reacting a 3'-'oxygenate' l bisnorcholan-22-al with a cyclic amine, such as pipei'idine, pyr-rolidine, morp'ho'line, homomorpho'line, 2- methyloxa-zolid-ine, trimethylenimine, or with another secondary amine such as dialkylamin'e, dicycloalkylamine, alkyl aralkylalnin'e, dialkanoylaniine or diara-lkylamine other 3-oxygenated-22-(N-tertiaryarnino) -bisnor-20( 22 cholerie are prepared such as 22'-(N-py'rrolidino)-bisnor- 4,20( 22) -choladien-3-one, 22- (N-honlomorpholino -bisnor-4,2'0'( 2-2) -choladien-*3-one, 22- (N-trimethyle'nimino') bisnor 4,-20(22) ch'ola'di'en 3 one, 22 (N tetrahy drbisoquinolino) 4 bisnor- 4=,2()(22) chol'adien 3 one, 3 acetoxy 9(11) 4 oxido 22 (N pyrrolidino) bisner=-5, 7,2d(2-2-)-cirblatrien 5,8 diinethyl maleate addu'c't, 3 phenylacetoxy 22 (N morpholino) bisnor 4,20 (22) choladin, 22 (tetrahydroisoquinoline) bisnor- 20(22) cholen 3 one, 22 [N (N dicyclohexylamiiioll bisnor-3B-tnethoxy=20(22)-cholen, ZZ EN-(N-didodecylamino)] bisnor 3 naphthoyloxy 20(22)- cholen, 3-hydroxy-22- (NJ-methyloxazolidino)-bisnor-5, 20(22) choladien, 22 k (N 'pyrrolidino) bisnor- 20(22)-eh len-3-one, 5,8-diethyl maleate adduct of- 3- acetoxy 22 [N (N diethanolamino)] bisnor 5,7, 20(22)-cholatrien, and the like.

mixture of 3.3 grams of"3,1l-diketobisnorA-cholenic acicl obtained by chromic acid oxidation of 3-ket'obi snor- 1 1u,22-dihydroxy-4-cholene, Murray and Petersomb'. S. Patent 2,602,769,; issued July 8, 1952 and ten milliliters of oxalyl chloride in benzene was maintained at room temperature for sixteen hours inthe presence ofpyridine. The excess of oxalyl chloride was eliminated by distilla tion under reduced pressure.

The thus-obtained 31,1l-diketobisnor 4-cholenic acid cuisine was arenreduced to'the aldehyde by the'iiiethod of Weygan'd et a1. tAn'gew. Chem. 65, 525 (1953)]. For this purpose, the crude (and cooled) 3,1I dik'tobisnor-4-cholenic acid chloride was dissovled-in lO0'milliliters of benzene and to this solution was added 4.5 milliliters of methylaniline, a four-fold excess of methylaniline; Themixture was heated for ten minutes on the water bath, cooled and thereafter transferred to a separatory funneL- The cooled benzene solution was washed successively with three five-milliliter portions of water, a fifteen-milliliter portion of five percent hydro chloric acid, afifteen-milliliter portion of five persent sodium hydroxide solution and five-milliliter portions of water until-the wash-water was neutral tophenolphthalein. The benzene solution was then evaporated and the product, 3,11-diketobisnor-4-cholenic acid methyl'anilide was once recrystallized from methanol and water.

The 3,11-diketobisnor-4-choleiiic acid methylanilide thus-obtained, admixed with three milliliters of distilled ethylene glycol, 150 milligrams of parartolue'nsulfonic said and sixty milliliters of benzene was placed in a reactionflask equipped with a reflux condenser and a water trap. The mixture 'was heated under reflux with stirring for ten hours. The water which was formed was removed by c0'-distillation with benzene and collected in the water trap. The reaction mixture was cooled, washed with dilute sodium bicarbonate solution and with water, dried, and evaporated under reduced pressure to give after two recrystallizations from ethyl acetate-Skellysolve B (hexanes), a white crystalline residue 3-ethylene ketal of 3,1l-dike'tobisnor-5-cholenic acid 'rr'lethylanilide.

To a solution of 1.2 grams of lithium aluminum hydride, dissolved in milliliters of anhydrous ether, was added dropwise the thus-obtained 3-ethylene ketal of 3,11=diketobisnor-5-cholenic acid methylanilide dissolved in 35 milliliters of tetrahydrofuran. The resulting mixture was stirred for one-half hour at a tempeiature of zero to five degrees centigrade, thereafter for one hour at room temperature (about 25 degrees centigrade) after which time it was refluxed for another hour and then cooled and hydrolyzed with fifteen milliliters of water. The organic layer was separated by dccantation and the remaining paste was suspended in water and repeatedly extracted with methylene dichloride. The combined ether and methylene dichloride solutions were concentrated to give crystalline 3-ethylene ketal of 3ketobisnor-1 lfi-hydroxy-S-cholen-ZZ-al.

The thus obtained 3'-ethylene ketal of 3-ketobisnor- 11/8-hydroxy-5;cholen-22-al was then refluxed in a mixture of 100 milliliters of methanol, 25 milliliters of Water, and two mil1ili ters of sulfuric acid for a period of two hours. Thereafter the reaction mixture was neutralized with sodium bicarbonate solutionand poured into one liter of cracked ice. The thus obtained crystalline material was collected on filter and recrystallized from methanol and Skellysolve B to give pure 3-ketobisnor-11/3- hydroxy-4-cholen-22-a1. v 4

A mixture of two grains of 3'-l etobisn0r-1 1/3-hydroxy- 4 'chol'en-22 al, 50 milliliters of thiophene fr'ee benzene and two milliliters of piperidine was placed in a distilling flask equipped with a reflux condenser so arranged that the condensed vapo'rs passed through eight grams of ab sorb'ent alihydrol'ls aluminum oxide particles before returning to the reaction zone, and the mixture was heated under reflux for two hours under an atmosphere of nitrogen. The benzene was then removed at subat'mospheric pressure and the residue was thorou hly agitated with ten milliliters of methanol. The methanolic extract was then cooled to about four degrees Centigrade for a period of four houlfs filtered, and the filter cake washed with about one milliliter of cold methanol anddried to obtain 1 Ifl-hydroXy-ZZ-(N piperidyl)-bisnor-4,20(22) chdladie'n- 3 one.

2 2 (N-piperidyl)=bisnor-4,20(22)-ch0ladien-3,11 drone can be obtained by reducing the 3,11-'diketobisn0r'-4- cholenic acid chloride in the manner shown by Rosenmund, Ber. 51, 585 (1918) with hydrogen in the presence of a palladium barium sulfate catalyst. The thus obtained 3,11-diketobisnor-4-cholen 22 al is reacted with piperidine in the manner shown before to 'give the 22'- (N-piperidyD-bisnon l,20(22) ch0ladine-3, 1 l-dione.

11a hydroxy-22-(N-piperidyl)-bisnor 4,20(22) choladi'e'n-3-one is obtained by reacting 3,1l-dike'tobisnor-4 cholenic acid chloride with hydrogen in the presence of barium sulfate to obtain 3,1l-diketobis'nor-4-cholen-22-al, reacting the thus produced 3,11-diketobisnor-4-cholen-22- a1 with ethylene glycol to obtain the 3,22-di-(0,0-didxyethylene)-l1-ketobisnor-4-cholene, reducingthe thus obtained ketal with sodium in propanol as shown by He'rz'oget al., J. Am. Chem. Soc. 75, 270 (1953) to obtain 3',22-di-(0,0-dioxyethylene)-1 la-hydroxybisnorl chol'en and hydro'lyzing the 3 keta-l and the 22acetalgroups with a dilute miner-a1 acid to obtain 3-ketobisnor-1lot-hydroxy- 4'-cholen-22-al which by reaction with pipe'ridine in the 7 manner shown above produces l'lu-hydroxy 22 (N- piperidyl)-bisnor-4,20(22)-choladien-3-one.

Reduction of 3,11-diketobisnor-4-cholen-22-al with hydrogen in the presence of a palladium catalyst on zinc carbonate or palladium in a generally basic medium gives the corresponding 3,11-diketobisnorcholan-ZZ-al which may be converted to the corresponding 22-piperidino, morpholino, tetrahydroisoquinolino, oxazolidino, homomorpholino, pyrrolidino, and the like enamines, by the methods of Heyl and Herr given above.

Similarly other 22-enamines of B-hydroxy-l l-lleto or 3,1l-dihydroxybisnorcholen-ZZ-als are obtained by reducing the 3-keto position of available 3,1l-diketobisnor- 4-cholen-22-al or 3-keto-lla-hydroxy and 3-keto-11flhydroxybisnor-4-cholen-22-al ZZ-enamines with sodium borohydride.

Esterifying such compounds produces the corresponding 3-acyloXy-l1-keto and 3,1la-diacylorlybisnorcholem 22-al 22-enamines. Representative 22-(N-tertiaryamino)- bisnor-20(22)-cholenes thus obtained comprise: Ila-hydroxy-ZZ-(N-piperidyl)-bisnor-4,20(22)-choladien 3 one, 1la-hydroxy22(N-morpholinyl)-bisnor 4,20(22) choladien-3-one, 11a-acetoxy-22-(N-pyrrolidyl)-bisnor-4,20(22)- choladien-3-one, 22-(N hommorpholino)-bisnor-4,20(22)- choladiene-3, l l-dione; 3a,l 1 fl-dihydroxy-ZZ- [N-(Z-methyloxazolidino)l-bisnor 20(22) cholene; 305,110t-dlP1OPlO- nyloxy-22-[N-(N-tetrahydroisoquinolinyl)1-bisnor-20(22)- cholene; 30c butyryloxy-l lfl-hydroxy-ZZ-[N-(N-dibenzyL amino)l-bisnor-20(22)-cholene; 30c benzoyloxy 22 (N- piperidyl)'bisnor-4,20(22)-choladien-1l-one; 3a-(2-furoyloxy)-22-(N-morpholinyl)-bisnor-20(22)-cholen ll one;, 3wnicotinyloxy-2Z-(N-piperidyl)-bisnor 4,20(22) choladien-l l-one, and the like.

PREPARATION 3 3 {3,6 fi-dihydroxy-ZZ-(N -piperidyl) -bisn0r-20 (22 -ch0lene In the manner shown in Preparation 2, 3-acetoxy-6- ketobisnorcholanic acid, prepared by the manner of Herbert O. Smith et al., J. Org. Chem. 19, 1628 (1954), when reacted with oxalyl chloride produced the 3-acetoxy- 6-ketobisnorcholanic acid chloride. Using the method of Weygand et al. [Angew. Chem. 65, 525 (1953)] to reduce the 3-acetoxy-6-ketobisnorcholanic acid chloride yields the 3,8,6/3-dihydroXybisnorcholan-2Z-aldebydes which is reacted as shown in Preparations 1 and 2 by the method of Heyl and Herr with piperidine to give the corresponding 313,618-dihydroxy 22 (N piperidyl) bisnor 20(22)- cholene.

By treatment of the 3p ,6li-dihydroxybisnorcholane aldehyde with acyl chlorides or acyl bromides the corresponding acyloxy esters are obtained such as, for example, the diacetoxy, dipropionyloxy, dibutyryloxy, divaleryloxy, dihexanoyloxy, dibenzoyloxy, disalicyloyloxy, dihemifumaryloxy, di-(2-furoyloxy), dinicotinyloxy, and the like. Such 35,6 8-diacyloxybisnorcholan aldehydes can be converted to the corresponding ZZ-enamines by the beforementioned methods.

Oxidation of 3,3,6 3-dihydroxybisnorcholan aldehyde ZZ-enamines by Oppenauer oxidation produces the corresponding ZZ-(N-tertiaryamino) bisnor 20(22) cholene- 3,6-diones. Reduction of the 3- and. 6-diketo groups with sodium borohydride produces the corresponding 3 x,6adihydroXy-22-(N-tertiaryamino)-bisnor-20(22)-cholenes.

In the manner shown in Preparation 3, the other 3,6- 3."

dioxygenated 22-(N-tertiaryamino)-bisnor-20(22)-cholenes are produced such as illustratively: 35,6,6-dihydroxy-22- (N-morpholinyl)-bisnor-20(22)-cholene, 35,6B-diacetoxy- 22-(N-pyrrolidyl)-bisnor 20(22) cholene, 35,613-dipropionyloxy-22-(Npiperidyl)-bisnor 20(22) cholcne, 358,6{3- dibutyryloxy 22 (N-piperidyl)-bisnor 20(22) cholene, 313,65 dibenzoyloxy 22 (N-piperidyl) bisnor 20(22)- cholene, 3 5,6,8 diphenylacetoxy-22-(N-piperidyD-bisnor- 20(22)-cholene, 313,6,8 dicinnamyloxy 22 (N -piperidyl)- bisnor-20(22)cholene, 30 6a-ditoluyloxy-22-(l l-piperidyl) bisnor-20(22)-cholene, 3a,Ga-dinicotinyloxy-22-(N-piperidyl)-bisnor-20(22)-cholene, 3u,6a-di-(2-furoyloxy)-22-(N- piperidyl)-bisnor-20(22)-cholene, 3u,6a-di-chloroacetoxy- 22-(N-piperidyD-bisnor 20(22) cholene, 22-(N rnorpholinyl)-bisnor-20(22)-cholene-3,6-dione, 22 (N-piperidyD- bisnor-20(22)-cholene 3,6 dione, 22 (N -homomorpholinyl) bisnor-20(22)-cholene 3,6 dione, 22-(N-tetraisoquinolinyl)-bisnor-20(22)-cholene-3,6-dione, 22-(N-oxazolidinyl)-bisnor-20(22)-cholene-3,6-di0ne, and the like.

EXAMPLE 1 3-ket0-20-br0m0bisnor-4-ch0len-22-al A solution containing 39.6 grams (0.1 mole) of 22-(N- piperidyl)-bisnor-4,20(22)-choladien-3-one, dissolved in 1200 milliliters of methylene chloride was cooled to a temperature of about minus 25 degrees centigrade. To this solution was added sixteen grams of bromine, dissolved in 100 milliliters of carbon tetrachloride, over a. period of twenty minutes while stirring. The reaction mixture was thereupon warmed to about zero degrees centigrade and 300 milliliters of cold water was added and the mixture was stirred for a period of an additional three hours. The organic layer was separated, washed twice with 300 milliliters of water, dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure. The thus-obtained residue weighed 40.1 grams (theory=40.7 grams) and was mainly 3-keto-20-bromobisnor-4-cholen-22-al of melting point to 110. This material was recrystallized twice from methylene chloride-Skellysolve B hexanes to give pure 3-keto-20-bromo bisnor-4-cholene-22-al of melting point 124 to 126 degrees centigrade.

Analysis.Calcd. for C H BrO C, 64.86; H, 7.67; Br, 19.62. Found: C, 64.90; H, 7.58; Br, 19.69.

Ultraviolet absorption max. is at 241.5 mu, k=42.56

EXAMPLE 1A 22 (N piperidyl) bisnor 4,20(22) choladien 3- one dibromide A suspension of 11.87 grams of 22-(N-piperidyl)-bis nor-4,20(22) -choladien-3-one, dissolved in 300 milliliters of peu'oleum ether, was cooled to a temperature of about minus 78 degrees centigrade. A solution of 4.80 grams of bromine, dissolved in fifty milliliters of methylene dichloride, was added dropwise under stirring over a period of about thirty minutes. Thereafter the mixture was concentrated to dryness in vacuo, leaving 16.40 grams of 22-(N-piperidyl)-bisnor-4,20(22)-choladien-3-one dibromide.

Analysis.-Calcd. for C2qH41B1'gNO: Br, 28.70. Found: Br, 29.23.

EXAMPLE 1B 3 keto 20 bromobisnor 4 cholen 22 al from 22 (N piperidyl) bisnor 4,20(22) choladien- 3 one dibromide A solution of 11.11 grams (20 millirnoles) of 22-(N- piperidyl)-bisnor-4,20(22)-choladien-3 one dibromide, dissolved in fifty milliliters of 95 percent ethanol, was allowed to stand at room temperature (twenty to thirty degrees Centigrade) for a period of three hours. Thereafter the dark solution was diluted with milliliters of methylene chloride and was washed with six 25-rnilliliter portions of water. The solution was then dried with ten grams of anhydrous sodium sulfate and concentrated to dryness in vacuo, leaving 6.90 grams of residue. Recrystallization from acetone yielded 4.35 grams (53.3 percent) of 3-keto-20-bromobisnor-4-cholen-22-al of melting point 126 to 129.

EXAMPLE 2 3-ketobisn0r-4,I7-choladien-22-al A solution of 40.7 grams (0.1 mole) of 3-keto-20- bromobisnor-4-cholen-22-al in 200 milliliters of pyridine was heated to a temperature of about seventy degrees centigrade for approximately one hour and thereafter on the steam bath for an additional hour. The solution was then concentrated in vacuo using continuous stirring, until a thick slurry was obtained. The slurry was dissolved in 200 milliliters of methylene chloride, washed twice with water, twice with dilute acid, once with. aque ous sodium hydroxide and with water. After drying over anhydrous sodium sulfate, ten grams of Florisil magnesiurn silicate was added and the mixture was agitated for a period of ten minutes. After filtration and concentration of the filtrate, 30.6 grams of crude 3-ketobisnor- 4,17-choladien-22-al was obtained. Chromatography over Florisil and evaporation of petroleumether-acetone eluant gave fractions melting at 136 to 149 degrees centigrade. These fractions when recrystallized from acetone had a melting point of 139 to 141.

Analysis.-Calcd. for C H O C, 80.93; H, 9.26. Found: C, 80.87; H, 9.23.

EXAMPLE 3 give 4-andr0stene-3J7-dione A solution containing 1.42 grams (4.36 millimoles) of 3-ketobisnor 4,l7(2()) choladien 22 al, 100 milliliters of ethyl acetate, 100 milliliters of methylene chloride and two milliliters of pyridine was placed in a tubular ozonization flask equipped with sparger and cooled to zero degrees centigrade. A stream of ozone containing 0.22 millimole of ozone per minute. was used, thesozonization time being 22 minutes. The total amount of ozone as consumed was 4.8 millimoles. Thereafter the contents of the ozonizationflask were transferred. to a round bottom flask and twenty milliliters of water was added. The mixture was warmed to reflux for a period of one and one-half hours. Thereupon the mixture was cooled, the layers were separated and the organic layer'was washed with Water. The water layer yielded py-ruvic aldehyde, while the organic layer after careful evaporation of the solvent yielded 0.75 gram of residue which was chromatographed over 75' grams of Florisil to give 0.28 gram of 4-androstene 3,17-dione of melting point 171 to 172 degrees Centigrade.

A preferred and generally used method is the decomposition of the ozonide by zinc and acetic acid.

EXAMPLE 4 3 a-acemxy-ZO-bromobisnorchohm-ZZ-al A solution containing 3.14 grams (7.1 millimoles) of 3a-acetoxy-22- (N-piperidyl) -bisnor-20 22.) -cholene in 20.0 milliters of ethyl acetate was cooled to about eight degrees centigrade. To this solution was added under stir.- ring 12.7 milliliters of a bromine. solution in carbon tetrachloride containinga total of.6..4 millimoles. of bromine. The bromine solution was addedv slowly and the addition was continued until the bromine. color persisted for one minute. In this manner a precipitate. was formed which was removed by filtration The filtrate was washed with water and dried over sodium sulfate. Evaporation of the solvent at reduced pressure yielded 3.07 grams of 3a, acetoxy 2O bromobisnorcholan '22 a1. Recrystallization from acetone gave a pure. 3a.-acetoxy-2.0- bromobisnorcholan-ZZ-al of melting point. 131, to 132 dc.- grees centigrade.

Anc lysis.-Calcd. for (3 1 1 1310 C, 63.56.; H, 8.22; Br, 17.62. Found: C, 63.65; H, 8.13;,Br, 16.947.

Otherwise like Example 4, other 3aand 3fl-acjyloxy- 22-.(N-tertiaryam ino) -bisnor-20(22 -cholene wherein the tertiaryamino radical and the acyloxy group are defined as above may be brominated. to give the corresponding 3aacyloxy-20-bromobisnorcholan-22-als. Representative of such compounds are the 3w and 313-acylxybisnor-20 bromocholan-ZZ-als wherein the acyloxy group is formyl- 10 oxy, propionyloxy, hntyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, hexanoyloxy, heptanoyl'oxy, octanoyloxy, benzoyloxy, (,8. cyclopentaylpropionyloxy), dimethylacetoxy, trimethylacetoxy, phenylacetoxy, toluyloxy, anisoyloxy, gallyloxy, salicyloyloxy, cinnamyloxy, hemisuccinyloxy, hemitartaryloxy,.dihydrogencitryloxy, maleyloxy, hemifumaryloxy, crotonyloxy, aerylyloxy, ,8.- methyl crotonyloxy, cyclohexanecarbonyloxy, dichloroacetoxy, trichloroacetoxy, bromoacetoxy, hemiquinolinoyloxy,

nicotinyloxy, piperonyloxy, 2 furoyloxy,.thioglycollyloxy,

para-chlorobenzoyloxy, para-bromobenzoyloxy, metanitrobenzoyloxy, 3,5-dinitrobenzoyloxy, benzenesulfonyloxy, para-chlorobenzenesulfonyloxy, para toluenesulfonyloxy, para nitrobenbenesulfonyloxy, 3,5 dinitrobenzenesulfonyloxy, benzenephosphonyloxy, and the like.

EXAMPLE 5 3a-acetoxybisn0r-J 7(20) -ch0len-22-al A solution of 4.53 grams (ten millimoles) ofv 3onacetoxy 20 bromobisnorcholan 22 al, dissolved in 25 milliliters of pyridine, was heated for a period of two hours on a steam bath. Thereafter the mixture was concentrated under reduced pressure to a solid residue. The residue was dissolved in 160 milliliters of ether and fifty milliliters of, water. After separation of the layers the ether solution wasv washed with 25 milliliters of, water, 25 milliliters, of ten percent, hydrochloric acid solution, and two 25-milliliter portions of Water. The solution was thereupon dried over anhydrous sodium sulfate, filtered and concentrated to a volume of about. five milliliters. Thereafter the solution was diluted with an equal volume of Skellysolve A hexanes and. refrigerated. The first crop of crystals, 2.58 grams, 69.3 percent of melting point 124 to 132 was reerystallizedfrom ether Skellysolve A and; gave pure 3a-aceteXybisnor-1- 7(20)-cholen-22-al of melting point 151- to 1 54 degrees Centigrade.

Analysis. Calcd. for C24 3693; C, 77.37;; H, 9x74. Found: C, 77.52, 77.38; H, 9.52, 9.21.

EXAMPLE 5A Dehydrobremimztion. of 3aaacetoxy-wwbromobisnorchollZIlvZZ-tll. in. the presence of lithium chloride to form 3a-aceloxyb isnor-l 7(20) -ch0len-22-al A solution of 4.53'grams (ten millimoles) of- 3a-acetoxy- 20-bromobisnorcholan-ZZ-al and 1.27 grams (30 mil-limoles) of anhydrous lithium chloride in 12.5 milliliters of dimethylformamide was heated for a period oftwo hours in a nitrogen atmosphere on a steam bath. The solution was diluted with 125 milliliters of water, and the gummy solid which precipitated was triturated with severalportions of water. Thereafter the residue wasdissolved-in -millilitersof ether, the solution washed'wi-th four 25I-rnilliliter portions of water, dried with five grams of anhydrous sodium sulfate, and'concentrated to about five milliliters of volume. This solution was thereupon diluted with five milliliters of Skellysolve A hexane hydrocarbons and refrigerated. A crop of 2.43 grams (65.2 percentyof 3a-acetoxyhisnor-l7(20 )eholen-22ral was obtained which could: be recrystallized from Skellysolveether rznzixtlures; to give the pure 3a-acetoxybisnor-l7(20)-cholen EXAMPLE 5B Dehydrobromination of 3a-acetoxy-ZO-bromobisnorch0- lan-22-al with semicarbazide hydrochloride to give 3aacetoxy bisn0r-1'7 (20) -cholen.-2'2-al To a solution of 2.23 grams of semicarbazide, hydro.- chloride and 1.64 grams of anhydrous sodium acetate, dissolved in ten milliliters of water, was added 4.5 3 grams of 3a-acetoxy-20-bromobisnorcholanr22-al in fifty inilliliters of di'oxane in a nitrogen atmosphere. The mixture was stirred'and heated at 45 degrees for a period. of twenty minutes. After theoriginal yellow solution became color.- less, five grams of pyruvic acid was added. The mixture thereupon was heated to 65 degrees centigrade for a '1 1 period of two hours. The reaction mixture was then concentrated to a volume of ten milliliters at reduced pres sure. The thus obtained syrupy liquid-was shaken with 100 milliliters of water and the mixture was extracted with 350-milliliter portions of ether. The extracts were washed with 25 milliliters of water, two 25-milliliter portions of ice cold ten percent sodium hydroxide solution, 25 milliliters of ten percent hydrochloric acid solution and two 25-milliliter portions of water. The yellow ether solution was dried with five grams of sodium sulfate, filtered and concentrated to five milliliters. Dilution with five milliliters of Skellysolve A pentane hydrocarbons and refrigeration yielded 0.45 gram of crystals of melting point 140 to 148 degrees centigrade which was purified by recrystallization as shown in Example 5.

The resinous residue (3.06 grams) contained the cor responding 3-hydroxy compound resulting from hydrol ys1s.

Otherwise like Examples 5, 5A and 5B, 3a-hydroxybisnor-ZO-bromocholen-ZZ-al or esters thereof such as 30:- or 3 fl-formate, propionate, butyrate, isobutyrate, valerate, isovalerate, hexanoate, heptanoate, octanoate, benzoate, phenylacetate, anisate, toluate, cinnamate, chloroand bromoacetate, trichloroacetate, hemisuccinate, hemitartrate, hemimaleate, dihydrogencitrate, can be dehydrobrominated with a tertiary amine such as pyridine, collidine, dimethyl aniline, trimethylamine and other tertiary amines or with dimethylformamide in the presence of a lithium salt such as lithium chloride, lithium bromide, or with semicarbazide and pyruvic acid to give the corresponding S-hydroxyor 3-acyloxybisnor-17(20)-cholen- EXAMPLE 6 3a-acetoxyeti0cholan-17-0ne In the manner given in Example 3, substituting for 3-,

ketobisnor-4,17-choladien-22-al in the ozonolysis 3a-acetoxybisnor-l?(20)-cholen-22-al results in 3aacetoxyetiocholan-17-one.

Substituting for the 3-ketobisnor-4,17-choladien-22-al in the ozonolysis 3aor 3B-hydroxybisnor-17(20)-cholen-22 a1 or any of the 3aor 3 fi-esters named in Example 5 such as the propionate, butyrate, hexanoate, heptanoate or other esters of the corresponding 3uor 3{3hydroxybisnor- 17(20)-cholan-22-als produces the corresponding 3::- or 3fl-hydroxyetiocholan-17-ones or respectively the corresponding 3aor 3 3-acyloxyetiocholan-17-ones, wherein the acyloxy groups are the same as shown in Example 4.

EXAMPLE 7 35,6fi-dihydroxybisnor-20-bromocholan-ZZ-al In the manner given in Example 1, 3fl,6B-dihydroxy- 22-(N-piperidyl)-bisnor-20(22)-cholen, dissolved in ethyl acetate was treated with bromine to give 35,6;8-dihydroxybisnor-20-bromocholan-22-al.

EXAMPLE 8 3,3,65-dihydroxybisnor-17(20 -cholen-22-al In the manner given in Example 2, 35,6;3-dihydroxybisnor-ZO-bromocholan-22-al was dehydrobrominated with pyridine to give 3,8,6l3-dihydroxybisnor-17(20)-cholen- 22-al.

EXAMPLE 9 3 fififl-dihydroxyetiocholan-I 7-one EXAMPLE 10 3-ket0allobisnor-20-chl0r0cholan-22-al Treating a solution of 22-(N-morpholinyl)-allobisn0r- 20(22)-cholen-3-one with a solution of chlorine in carbon tetrachloride cooled to zero degrees centigrade produced a 3-ketoallobisnor-ZO-chlorocholan-22-al.

EXAMPLE 11 3 -ket0all0bisnor-1 7(20) -cholen-22-al In the same manner as shown in Example 2, 3-ketoallobisnor-ZO-chlorocholan-ZZ-al was treated with colli- I dine to produce 3-ketoallobisnor-l7(20)-cholen-22-al.

EXAMPLE 12 Andr0stane-3,17-dione In the same manner as shown in Example 3, ozonizing 3-keto-allobisnor-17(20)- cholen-22-al yields androstane-3,l7-dione.

EXAMPLE 13 3,11-diket0bisnor-20-bromo-4-cholen-22-al In the same manner as given in Example 1, treating ZZ-(N piperidyl)-bisnor-4,2O(22)-choladien 3,11 dione with a solution of bromine produces 3,11-diketobisnor-20- bromo-4-cholen-22-al.

EXAMPLE 14 3,I1-diket0bisn0r-4,17(20 -ch0ladien-22-al In the, same manner as shown in Example 2, dehydrobrominating 3,11 diketobisnor 20-bromo-4-cholen-22-al with dimethyl formamide in the presence of lithium bromide yielded 3,11-diketobisnor-4,17(20)-choladien-22-al.

EXAMPLE 15 4-andr0stene-3,11,1 7-trione Ozonolyzing 3,11 diketobisnor-4,I7(20)-choladien-22- al in the manner shown in Example 3, produced 4-androstene-3 ,1 1,17-trione (adrenosterone) Substituting for the 22-(N-piperidyl)-bisnor-4-cholen- 3-one of Example 1, 11a-hydroxy-, llp-hydroxyor 1111- acyloxy 22 (N-piperidyl) -bisnor-4,20(22)-chloadien-3- one, the corresponding 3-ketobisnor-llahydroxy-, 3- ketobisnor--hydroxy-, or 3-ketobisnor-l1u-acyloXy-20- bromo-4-cholen-22-al, wherein the acyloxy group is of an organic carboxylic, preferably of a hydrocarbon carboxylic acid containing from one to eight carbon atoms as listed in Example 4, are obtained.

Substituting for the 3-ketobisnor-20-bromo-4-cholen- 22-al of Example 2, 3-keto-1la-hydroXy-, 3-keto-11flhydroxy-, or 3-keto-11a-acyloxy-20-brom0bisnor-4-cholen-22-al results in the corresponding 3-ketobisnor-l1ahydroxy-, 3-ketobisnor-1lB-hydroXy-, or 3-ketobisnor- 11a-acyloXy-4,17(20)-choladien-22-al wherein the acyloxy groups are defined as stated hereinbefore.

Ozonolysis of 3 ketobisnor 1la-hydroxy-4,l7(20)- choladien-ZZ-al according to the procedure shown in Example 3, produces l1a-hydroxy-4-androstene3,17-dione.

Ozonolysis of 3 ketobisnor 11 8-hydroxy-4,l7(20)- choladien-22-al produces 11fi-hydroxy-4-androstene-3,17 dione.

, l3 vOzonolysis of 3 .-lgetobisnr-lla acyloxye l,17(20)=chovwith 200 milliliters of water containing five grams of sodium bisulfite, cooled to about zero degrees centigrade and herevaqn l e edhe pre a hus bt e Y e ease by luu tou t m wi fi -m l te p ia ri te nd d d in a Yasm n ec q hi teria recr stalliz om et e m hylene chlofiit s r Pur w t -c stals.of i1s 11 i nor- Q PWEQ QlW T Zr J- n the. Same manner as given in Example 2, 3,11-diketoallobisnor-2,0;bromocholan-22-al .was refluxed in triethanolamine to, give 3,11 diketoa1lobisnor-17(20)-cholen- 22-al.

EXAM??? ttd e tqna-ilLlZvt iQne In the same manner as given in Example 3, 3,11-diketoallobisnor-17(20)-ch01en-22-al was ozonized to yield andros tane-3,"11,17-'trione.

Substituting for the 22-(N-tertiaryamino)-allobisnorcholane- 3,l1-dion e the normal compounds, 2-2-N-pyrrolidylbisnorcholane-3,1l-dione, the corresponding normal bisnorcholane bromide, 3,1l:diketobisnor-ZO-bromocholan-22-al is obtained.

Substituting for the allobisnorcholane compound of Example 17, the normahbisnorcholane compound, 3,11- diketobisnor-20-br.omocholan-22-al, the corresponding 3,- 11-dil etobisnor-17 (20)1cholen-22-al is obtained byv dehydrohalogenation as shown in Example 2.

Ozonizing 3,1'1-diketobisnor-1-7(20)-cholen-22-al in the manner shown in Example 3, produces etiocholane-3,l1,- 20.-t'riohe.

EXAMB P 9 In the. ma er given in Examp e 1, b 9m n ne= 114 cet xy 1(N.-P P. ridY )r l QQ Q chs eu -s ne produc s .:ketQb nQ lee e xwQ-b m c o1an:22:

1 -1 h oxy 2 1(N-P P Y )#b S l1 Q( hQ1en- -pn produces o hi B-hY IQ Y- -bmmocholan 22 al.

(d) 30: acetoxy 22-(N-homomorpholinyl) bisnor- 5,2Q(22)-ch oladine produces 3aracetoxybisnor-ZO-bromo- 5-,cholen-22-al. V

(2)312: hydroxy ZZ-(N-piperidyl)-bisnor-5,20(22)- choladiene produces 3u-hydroXybisnor:20:bromoricholen-22-al.

(f) 35 acetoxy 6 nitro-22-(N-piperidyl)-bisnor- 5,20(22)-choladiene produces 3,8-acetoxybisnor-G-nitro- -bromo-5-cholene. r

(g) 3-keto-9,l1-oxido 22;(N-pyrrolidyl)-bisnor-5,7,20-

' ehydrie e des P emise sis-ease al e iate.

14 22 N-(irmetbxl z aql yl) -b snQr 4,2 (22)- iifir l t n P oduce 3.6, -t -iketobisnor-20- olen- 22-a EXAM LE 20 in th sa e arme assh w xamp e ydr mmi ati wit a tertiary uch a N- me y an lin p rid ne. s llidin a 1 or v-p qlin et ahyltq s ui ol n l rimeth latnia and e l (q) 3 ketobisnor-l 1a-hydroxy 20ebromocholanQZ-al produces 3 lgeto-11u-hydroxybisnor-lflw)w-cholen-22-al. .(b) .3 k t nor- 1a: t;etQxy-20:brom9hQ1an-2Z-a I1 i 9$ 3 ke -llgacetox bi n 00)-c o 2- (d) 30: acetoxybisnor-ZO-bromo-S-cholen-ZZ-al produces 3a-acetoxybisnor-5,l7(20).-cl1oladien-22-al.

(e) 3 0; hydroxyb' n or-20-bromori-cholen-22eal pro- (1) 3oz acetoxybispor .6 nitro 20 bromo 5- cholen-22-al produces fia acetoxy:nitrobisnor-S,17(20)- choladien-22 al.

(g). 3 ketobisnor 9 (11) oxido 20 bromo 5,7- choladien-22-al 5,8-ma1eic anhydride adduct produces 3- ketobisnor-9( 1 1 -oxido- 5,7, 1 7.(2 0) -cholatrien-22-al 5,8- m l enh d d d u (h) 3,6,11 triketobisnor 20 bromo 4 cholen- 2- 11 M ifie 3 61 lk i n r-efl( o ad en- 22- EKAMRL 12 In the same manner as given in Example 3, ozonizing: (a) 3 ketobisnor 11cc hydroxy 17(20) cholen- 22-al produces 11u-hydroxyetiocholane-3,17-dione.

(b) 3 ketobisnor 11a acetoxy 17(20) cholen- 22-al produces 11a-acetoxyetiocholane-3,l 7-dione.

(c) 3 ketobisnor 11/8 hydroxy 17 ('20) cholen- 22-al produces 1lfi hydroxyetiocholanefi,17-dione.

(11) 3o: acetoxybisnor 5, 17(;2 0) choladien 22 a1 produces 3u-acetoxy-5-androsten-17-one (dehydroandrosterone acetate).

(e) '30: hydroxybisnor 5,17'(20) choladien 22 a1 produces 3a-hydroxy-5-androstene-17-one (dehydroandrosterone) V (1) 3a acetoxybisnor 6 nitro 5, 17(20) choladien- 22-al produces 3a-acetoxy-o-nitro-5-androsten-17-one.

(g) 3 ketobisnor 9(11) oxido 5,7,17(20)-cholatrien-22-al 5,8-maleic anhydride adduct produces 9(11)- oxido-S,7-androstadiene-3,17-dione 5,8-maleic anhydride adduct.

(h) 3,6,11 triketobisnor 4,l7(20) choladien 22- al produces 4-androstene-3,6,11,l7-tetraone.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the lnvention is therefore to be limited only by the scope of the appended claims.

I c a m:

1, A 20,-halobisnorcholan-22-al seleced from the group consisting of 3-ketobisnor-20rhalo-4-cholen-22-al; 3-keto- ?QI- Q- aIOChQIamZLaI; 3-ketoallobisnor-ZO-halocho- Ian-22ml, 3-hydroxybisnor=20-halocholan-22-a1 and 3-acyloxybisnor 20 halocholan 22 al; 3 hydroxyallobisnor 20 halocholan 22 al-and 3-acyloxyallobisnor-20- QChOlan 22 al, 3 hydrox-ybisnor 20 halo 5- cho1en,2 2;al and 3eacyloxybisnor-ZO-halo-S-cholen-22-al; 3, 11 7 diketobisnor 20. halo -.4 --cholen 22 al, 3- keto'bisnor 7 hydroxy 20 halo 4 cholen 22 al, 3-ketobisnor-11 ,6ehydr0xy 2O-halo-4-cholen-22-al and 3,6-diketobisnor-ZO-halogholan-ZZ-al, wherein the halogen 4 atom has an atomic weight of 34 to 81, inclusive, and

. 3-ketobisnor-20-bromo-4-cholen-22-al.

. 3,11-diketobisnor--bromo-4-cholen-22-al.

. 3a-acetoxybisnor-20-bromocholan-22-al.

. 3-oxygenated-l7 20 -bisnorcholen-22-al.

. 3-ketobisnor-4, 17 (20) -choladien-22-al.

. 3, l 1-diketobisnor-4, 17 (20) -choladien-22-al.

A process for the production of a ZO-halobisnorcholan-ZZ-al which comprises: treating a ZZ-(N-tertiaryamino)-bisnor-20(22)-cholene selected from the group consisting of ZZ-(N-tertiaryamino)-'bisnor-4,20(22)-choladien 3 ones, 22 (N tertiaryamino) bisnor- 20 (22) -cholen-3 -one, ZZ-(N-tertiaryamino -allobisnor- 20(22)-cholen-3-one, 3-hydroxyand 3-acyloxy-22-(N- tertiaryamino)-bisnor-20(22)-cholenes, S-hydroxyand 3 acyloxy 22 (N tertiaryamino) allobisnor- 20(22)cholen-3-one, 3-hydroxyand 3-acyl-oxy-22-(N- tertiaryamino) bisnor 5,20(22) choladien, 22-(N-tertiaryamino) bisnor 4,20(22) choladien 3,11 dione, ZZ-(N-tertiaryamino)-bisnor-20(22)-cholen-3,6-dione, wherein the acyl group is of an organic carboxylic acid having from one to eight carbon atoms and wherein the tertiaryamino radical is of the formula:

Clix-CH2 in which n and n are whole numbers from one to two, inclusive, with halogen of atomic weight 34 through 81, inclusive, at a temperature between about minus thirty and about plus twenty degrees centigrade to obtain the corresponding 20-halobisnor-cholan-22-al.

9. A process for the production of 3-ketobisnor-20- bromo-4-cholen-22-al which comprises: treating 22-(N- piperidyl)-bisnor-4,20(22)choladien3-one with bromine,

dissolved in an organic solvent, at a temperature between minus thirty and about plus twenty degrees centigrade to obtain 3-ketobisnor-ZO-bromo-4-cholen-22-al.

10. A process for the production of 3,11-diketobisnor- 20-bromo-4-cholen-22-al which comprises: treating 22- (N-pi-peridyl)-bisnor-4,20(22)-choladien-3-one with bromine, dissolved in an organic solvent, at a temperature between minus thirty and about plus twenty degrees centigrade to obtain 3,11 diketobisnor 2O bromo-4-cholen- 22-al.

11. A process for the productionof 3a-acetoxybisnor- 20-bromocholan-22-al which comprises treating 3u-acetoxy-22-(N-piperidyl)-bisnor-20(22)-cholen with bromine at a temperature between minus thirty and about plus twenty degrees centigrade to obtain '3a-acetoXybisnor-20- bromocholan-22-al.

12. A process for the preparation of a 3-oxygenated- 17(20)-bisnorcholen-22-al which comprises: treating a 3- oxygenated 22- (N-tertiaryamino -hisnor-20 22) -cholene wherein the tertiaryamino radical is of the formula:

CH2CH2 tis-1) CHt-(GHzh in which n and n are whole numbers from one to two, inclusive, with halogen of atomic weight 34 through 81, inclusive, between about minus thirty and about plus twenty degrees centigrade to obtain the corresponding 3- oxygenated 20-halobisnorcholan-ZZ-al and dehydrohalogenating the 3-oxygenated 20-halobisnorcholan-22-al through heating with a tertiary amine to obtain the corresponding 3-oxygenated-17(20)-bisnorcholen-22 al.

13. A process for the preparation of a 3-oxygenated- 17(20)-bisnor-cholen-22-a1 which comprises: treating a 3-oxygenated ZZ-(N-tertiaryamino)-bisn1or-20(22)-cholene wherein the tertiaryamino radical is CH2CH2 in which n and n are whole numbers from one to two, inclusive, with bromine in an organic solvent between about minus thirty and about plus twenty degrees centigrade to obtain the corresponding 3-oXygenated-20-bromobisnorcholen-22-al and dehydrohalogenating the 3- oxygenated-ZO-bromobisnorcholen-ZZ-al with pyridine at a temperature between about sixty and about degrees centigrade to obtain the corresponding 3-oxygenated- 17(20)-bisnorcholen-22-al.

14. A process for the preparation of 3-ketobisnor- 4,17 (20)-choladien-22-al which comprises: treating a 22- (N tertiaryamino) bisnor 4,20(22) choladien 3- one wherein the tertiaryamino group is CHr-CH:

in which n and n are 'whole numbers from one to two inclusive with halogen of atomic weight 34 through 81, inclusive, between about minus, thirty and about plus twenty degrees centigrade to obtain the corresponding 3-ketobisnor-20-halo-4-cholen-22-al and dehydrohalogenating the thus obtained 3-ketobisnor-20-halo-4-cholen-22- al thru heating with a tertiary amine to obtain 3-ketobisnor-4,17(20)-choladien-22-a1.

15. A process for the preparation of 3-ketobisnor- 4,l7(20)-choladien-22-al which comprises: treating 22- (N-piperidyl)-bisnor-4,20(22)-choladien-3-one with bromine in an organic solvent at a temperature between about minus thirty and about plus twenty degrees to obtain 3-ketobisnor-20-bromo-4-cholen-22-al and dehydrobrominating the thus obtained 3-ketobisnor-20-bromo-4- cholen-22-al with pyridine at a temperature of about sixty to about 100 degrees centigrade to obtain S-ketobisnor- 4,17(20)-choladien-22-al.

16. A process for the preparation of 3,11-diketobisnor- 4,17(20)-choladien-22-al which comprises: treating a 22- (N-tertiaryamino -bisnor-4,20 (22 -cho1adien-3,l 1 dione wherein the tertiaryamino group is in which n and n are whole numbers from one to two, inclusive with halogen of atomic weight 34 through 81, inclusive, between about minus thirty and about plus twenty degrees centigrade to obtain the corresponding 3,11 -diketobisnor-ZO-halo-4-cholen-22-a1 and dehydrohalogenating the thus obtained 3,1l-diketobisnor-ZO-halo- 4-cholen-22-al by heating with a tertiary amine to obtain 3,11-diketobisnor-4,17(20)-choladien-22-al.

17. A process for the preparation of 3,11-diketobisuor- 4,17(20)-choladien-22-al which comprises: treating 22- (N-piperidyl) -bisn0r-4,20 22) -choladiene-3,1 l-dione with bromine in an organic solvent at a temperature between about minus thirty and about plus twenty degrees centigrade to obtain 3,11-diketobisnor-20-bromo-4-cholen- 22-al and dehydrobrominating the thus obtained 3,11- diketobisnor-20-bromo-4-cholen-22-al with pyridine at a temperature between about sixty and about 100 degrees centigrade to obtain 3,11-diketo-bisnor-4,17(20)-choladien-22-al.

18. A process for the production of compounds selected from the group consisting of 3-oxygenated 17-ketosteroids of the androstane and etiocholane series, which comprises: treating a 3-oxygenated 22-(N-tertiaryamino)- bisnor-20(22)-cholene wherein the tertiaryamino radical in which n and n are whole numbers from one to two, inclusive, with halogen of atomic weight 34 through 81, inclusive, between about minus thirty and about plus twenty degrees centigrade to obtain the corresponding 3 oxygenated 20-halobisnorcholan-22-a1, dehydrohalogenating the 3 oxygenated 2O halobisnorcholen-ZZ-al through heating with a tertiary amine to obtain the corresponding 3-oXygenated-17(20)-bisnorcholan-22-al and ozonolyzing the thus obtained 3-oxygenated-17(20)bisnorcholan-22-al to obtain the corresponding 3-oxygenated 17-ketosteroid.

19. A process for the production of compounds selected from the group consisting of 3-oxygenated 17-ketosteroids of the androstane and etiocholane series, which comprises: treating a 3-oxygenated 22-(N-tertiaryamino)- bisnor-20(22)-cholene wherein the tertiaryamino radical in which n and n are Whole numbers from one to two, inclusive, with bromine in an organic solvent between about minus thirty and about plus twenty degrees centigrade to obtain the corresponding 3-oxygenated 20-brornobisnorcholan-ZZ-al, dehydrobrominating the 3-oxygenated 20-bromobisnorcholen-22-al at a temperature between about sixty and about 100 degrees centigrade with pyridine to obtain the corresponding 3-oxygenated bisnor- 17(20)-ch0len-22-a1 and ozonolyzing the thus obtained 3-oxygenated bisnor-17(20)-cholen-22-al to obtain the corresponding 3-oxygenated 17-ketosteroid.

20. A process for the production of 4-androstene-3,17- dione which comprises: treating 22-(N-piperidyl)-bisnor- 4,20(22)-choladien-3-one with bromine in an organic solvent at a temperature between about minus thirty and about plus twenty degrees centigrade to obtain 3-ketobisnor-20-bromo-4-cholen-22-al, dehydrobrominating the thus obtained 3-ketobisnor-20-bromo-4-cholen-22-al with pyridine at a temperature between about sixty and about 100 degrees centigrade to obtain 3-ketobisnor-4,17(20)- choladien-ZZ-al and ozonolyzing the thus produced 3-ketobisnor-4,17(20)-choladien-22-al to obtain 4-andr0stene- 3,17-dione.

21. A process for the production of adrenosterone which comprises: treating 22-(N-piperidyl)-bisnor-4,20- (22)-choladien-3,1l-dione with bromine in an organic solvent at a temperature between about minus thirty and about plus twenty degrees centigrade to obtain 3,11-diketobisnor-ZO-bromo-4-cholen-22-al, dehydrobrominating the thus obtained 3,11-diketobisnor-20-bromo-4-cholen- 22-al with pyridine at a temperature between about sixty and about 100 degrees centigrade to obtain 3,11-diketobisnor-4,17(20)-cho1adien-22-al, and ozonolyzing the thus produced 3,11-diketobisnor-4,17 (20)-choladien-22-al to obtain adrenosterone.

References Cited in the file of this patent UNITED STATES PATENTS 2,732,384 Beal Jan. 24, 1956 UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,844,605 July 22, 1958 Raymond L. Pederson It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, lines 23 to 26, the formula should appear as shown below instead of as in the patent same column 3, line 52, for -homorpholinyl read -homomorpholinyl-; column 5, line 34, for (tetrahydroisoquinoline) read (tetrahydroisoquiuolino); line 59, for dissovled read dissolved; line 67, for persent read percent-; column 6, line 61, for -choladineread -choladienecolumn 10, line 3, for cyclopentaylpropionyloxy read cyclopentylpropionyloxy; line 14, for -nitrobenbenesulfonyloxy read -nitrobenzenesulfonyloxy-; column 12, line 56, for -ch1oadienread -cho1adiencolumn 13, line 64:, for -choladine read -choladiene; column 14:, line 61, for seleced read se1ected.

Signed and sealed this 7th day of July 1959.

Attest= KARL H. AXLINE, ROBERT C. WATSON, Attesting Ofiaer. Uonwnissz'oner of Patents. 

1. A 20-HALOBISNORCHOLAN-22-AL SELECTED FROM THE GROUP CONSISTING OF 3-KETOBISNOR-20-HALO-4-CHOLEN-22-AL; 3-KETOBISNOR-20-HALOCHOLAN-22-AL; 3-KETOALLOBISNOR-20-HALOCHOLAN-22-AL, 3-HYDROXYBISNOR-20-HALOCHOLAN-22-AL AND 3-ACYLOXYBISNOR-20-HALOCHOLAN-22-AL; 3-HYDROXYALLOBISNOR-20-HALOCHOLAN-22-AL AND 3-ACYLOXYALLOBISNOR-20HALOCHOLAN-22-AL, 3-HYDROXYBISNOR-20-HALO-5CHOLEN-22-AL AND 3-ACYLOXYBISNOR-20-HALOS-5-CHOLEN-22-AL; 3,11-DIKETOBISNOR-20-HALO-4-CHOLEN-22-AL, 3KETOBISNOR-11A-HYDROXY-20-HALO-4-CHOLEN-22AL, 3-KETOBISNOR-11B-HYDROXY-20-HALO-4-CHOLEN-22-AL AND 3,6-DIKETOBISNOR-20-HALOCHOLAN-22-AL, WHEREIN THE HALOGEN ATOM HAS AN ATOMIC WEIGHT OF 34 TO 81, INCLUSIVE, AND WHEREIN THE ACYL GROUP IS OF AN ORGANIC CARBOXYLIC ACID CONTAINING FROM ONE TO EIGHT CARBON ATOMS, INCLUSIVE. 